Chemotherapy alone versus chemotherapy plus radiotherapy for adults with early-stage Hodgkin's lymphoma

Background: Early-stage Hodgkin's lymphoma in adults is commonly treated with combined modality treatment of chemotherapy followed by radiotherapy. The role of radiotherapy has been questioned due to potential long-term adverse effects.

Objectives: To assess the effects of chemotherapy compared to chemotherapy plus radiotherapy in adults with early-stage Hodgkin's lymphoma.

Search methods: We updated all previous searches for randomised controlled trials (RCTs) on the databases Cochrane Central Register of Controlled Trial, MEDLINE and Embase, in trial registries and in relevant conference proceedings until November 2023.

Selection criteria: We included RCTs comparing chemotherapy alone with chemotherapy plus radiotherapy in adults with early-stage Hodgkin's lymphoma and excluded trials with more than 20% of participants with advanced Hodgkin's lymphoma. We considered immunotherapy in addition to chemotherapy eligible if both were applied similarly in the comparator groups, but did not identify such trials. For our comparisons, we separated RCTs with the same number of chemotherapy cycles in both arms and RCTs with a different number of cycles, when the chemotherapy regimens were the same. We separated RCTs which compared participants with a favourable, mixed or unfavourable risk profile.

Data collection and analysis: Two review authors independently screened search results, extracted data and assessed the quality of included trials. A third review author resolved discrepancies. We analysed time-to-event outcomes (overall survival, progression-free survival) as hazard ratios (HR) and binary outcomes (adverse events) as risk ratios (RR). We assessed the certainty of evidence using the GRADE approach.

Main results: We included nine comparisons of eight RCTs involving 3840 participants in this updated review. Same number of chemotherapy cycles in both trial arms Favourable disease For overall survival in individuals with favourable Hodgkin's lymphoma, the evidence is uncertain and inconclusive (HR 0.92, 95% confidence interval (CI) 0.11 to 7.92; 2 RCTs, 1245 participants; very low-certainty evidence due to study limitations, inconsistency and imprecision). Additional radiotherapy to chemotherapy is likely to improve progression-free survival (HR 0.36, 95% CI 0.20 to 0.68; 2 RCTs, 1245 participants; moderate-certainty evidence due to study limitations). The evidence was uncertain and inconclusive for second-cancer-related mortality (RR 0.93, 95% CI 0.01 to 74.24; 2 RCTs, 1245 participants; very low-certainty evidence due to study limitations, inconsistency and substantial imprecision) and suggests little to no difference in cardiac disease-related mortality (RR 0.89, 95% CI 0.06 to 14.16; 1 RCT, 667 participants; low-certainty evidence due to substantial imprecision). There were no data on infection-related mortality or infertility. Mixed population For a population of mixed risk profile, the evidence on overall survival is uncertain and inconclusive (HR 0.79, 95% CI 0.13 to 4.80; 2 RCTs, 572 participants; very low-certainty evidence due to study limitations, inconsistency and imprecision). It indicates that additional radiotherapy may lead to an improvement in progression-free survival (HR 0.71, 95% CI 0.43 to 1.17; 2 RCTs, 572 participants; low-certainty evidence due to study limitations and imprecision). The evidence is uncertain and inconclusive for infection-related mortality (RR 1.35, 95% CI 0.17 to 10.87; 2 RCTs, 572 participants) and second-cancer-related mortality (RR 0.52, 95% CI 0.09 to 2.98; 2 RCTs, 572 participants) (both very low-certainty evidence due to study limitations and substantial imprecision), but suggests that additional radiotherapy may increase cardiac disease-related mortality (RR 3.03, 95% CI 0.12 to 73.92; 1 RCT, 420 participants; low-certainty evidence due to substantial imprecision). There were no data on infertility. Unfavourable disease For individuals with unfavourable disease, the evidence on overall survival is uncertain and inconclusive (HR 0.69, 95% CI 0.20 to 2.44; 2 RCTs, 688 participants; very low-certainty evidence due to study limitations and substantial imprecision), but additional radiotherapy probably improves progression-free survival (HR 0.55, 95% CI 0.19 to 1.60; 1 RCT, 651 participants; moderate-certainty evidence due to imprecision). The evidence was uncertain and inconclusive for cardiac disease-related mortality (RR 2.85, 95% CI 0.12 to 65.74; 1 RCT, 37 participants; very low-certainty evidence due to study limitations and substantial imprecision). There were no data on infection-related mortality, second-cancer related mortality or infertility. Different number of chemotherapy cycles in both trial arms Favourable disease The evidence for overall survival in individuals with favourable disease treated with different numbers of chemotherapy cycles in both arms is uncertain and inclusive (HR 0.36, 95% CI 0.04 to 3.38; 1 RCT, 357 participants; very low-certainty evidence due to study limitations and substantial imprecision), yet it suggests a likely improvement in progression-free survival with additional radiotherapy (HR 0.08, 95% CI 0.02 to 0.32; 1 RCT, 357 participants; moderate-certainty evidence due to study limitations). For second-cancer-related mortality, the evidence is uncertain and inconclusive (RR 0.21, 95% CI 0.01 to 4.34; 1 RCT, 465 participants; very low-certainty evidence due to study limitations and substantial imprecision). There were no data on infection-related mortality and infertility and data for cardiac disease-related mortality were not estimable (no events in either group). Unfavourable disease For individuals with an unfavourable risk profile, additional radiotherapy may decrease overall survival slightly (HR 1.66, 95% CI 0.95 to 2.90; 2 RCTs, 698 participants; low-certainty evidence due to study limitations and imprecision), but may slightly improve progression-free survival (HR 0.84, 95% CI 0.53 to 1.33; 2 RCTs, 698 participants; low-certainty evidence due to study limitations and imprecision). The evidence is uncertain and inconclusive for infection-related mortality (RR 6.90, 95% CI 0.36 to 132.34; 1 RCT, 276 participants), second-cancer-related mortality (RR 2.19, 95% CI 0.77 to 6.19; 2 RCTs, 870 participants) and cardiac disease-related mortality (RR 1.60, 95% CI 0.31 to 8.22; 2 RCTs, 870 participants) (all very low-certainty evidence due to study limitations and substantial imprecision). There were no data on infertility.

Authors' conclusions: The chemotherapy regimens in the trials differed and data for regimens commonly used today were limited. Additional radiotherapy may slightly improve progression-free survival. The available data for overall survival and adverse events were of low and very low certainty, and we were unable to draw conclusions about the effects of additional radiotherapy on these outcomes. No studies evaluated infertility. High-quality, longer-term follow-up data are required and data on fertility are needed.